tbuckley/cabot-search huggingface dataset:
The Singapore National Precision Medicine Strategy
Authors: Eleanor Wong, Nicolas Bertin, Maxime Hebrard, Roberto Tirado-Magallanes, Claire Bellis, Weng Khong Lim, Chee Yong Chua, Philomena Mei Lin Tong, Raymond Chua, Kenneth Mak, Tit Meng Lim, Wei Yang Cheong, Kwee Eng Thien, Khean Teik Goh, Jin-Fang Chai, Jimmy Lee, Joseph Jao-Yiu Sung, Tien Yin Wong, Calvin Woon Loong Chin, Peter D. Gluckman, Liuh Ling Goh, Kenneth Hon Kim Ban, Tin Wee Tan, Rob M. Van Dam, Yik Ying Teo, Marie Loh, Paul Eillot, Eng Sing Lee, Joanne Ngeow, Elio Riboli, Rinkoo Dalan, Irfahan Kassam, Lakshmi Narayanan Lakshmanan, Tock Han Lim, Hong Kiat Ng, Theresia Mina, Darwin Tay, Charumathi Sabanayagam, Yih Chung Tham, Tyler Rim, Tin Aung, Miao Ling Chee, Hengtong Li, Miao Li Chee, Khung Keong Yeo, Stuart Alexander Cook, Chee Jian Pua, Chengxi Yang, Yap Seng Chong, Johan Gunnar Eriksson, Kok Hian Tan, Fabian Yap, Chia Wei Lim, Pi Kuang Tsai, Wen Jie Chew, Wey Ching Sim, Li-xian Grace Toh, Clarabelle Bitong Lin, Yee Yen Sia, Tat Hung Koh, Wee Yang Meah, Joanna Hui Juan Tan, Justin Jeyakani, Jack Ow, Shimin Ang, Ashar J. Malik, Dimitar Kenanov, Xueling Sim, Ching-Yu Cheng, Sonia Davila, Neerja Karnani, Khai Pang Leong, Jianjun Liu, Shyam Prabhakar, Sebastian Maurer-Stroh, Chandra Shekhar Verma, Pavitra Krishnaswamy, Rick Siow Mong Goh, Irenaeus Chia, Clarissa Ho, Doreen Low, Suchin Virabhak, Jacklyn Yong, Weiling Zheng, Shih Wee Seow, Yee Kwang Seck, Mingshi Koh, John C. Chambers, E. Shyong Tai, Patrick Tan
Journal: Nature Genetics (2023)
Ferroptosis‐modulating small molecules for targeting drug‐resistant cancer: Challenges and opportunities in manipulating redox signaling
Authors: Solveigh C. Koeberle, Anna P. Kipp, Hermann Stuppner, Andreas Koeberle
Journal: Medicinal Research Reviews (2023)

Abstract Ferroptosis is an iron‐dependent cell death program that is characterized by excessive lipid peroxidation. Triggering ferroptosis has been proposed as a promising strategy to fight cancer and overcome drug resistance in antitumor therapy. Understanding the molecular interactions and structural features of ferroptosis‐inducing compounds might therefore open the door to efficient pharmacological strategies against aggressive, metastatic, and therapy‐resistant cancer. We here summarize the molecular mechanisms and structural requirements of ferroptosis‐inducing small molecules that target central players in ferroptosis. Focus is placed on (i) glutathione peroxidase (GPX) 4, the only GPX isoenzyme that detoxifies complex membrane‐bound lipid hydroperoxides, (ii) the cystine/glutamate antiporter system X c − that is central for glutathione regeneration, (iii) the redox‐protective transcription factor nuclear factor erythroid 2‐related factor (NRF2), and (iv) GPX4 repression in combination with induced heme degradation via heme oxygenase‐1. We deduce common features for efficient ferroptotic activity and highlight challenges in drug development. Moreover, we critically discuss the potential of natural products as ferroptosis‐inducing lead structures and provide a comprehensive overview of structurally diverse biogenic and bioinspired small molecules that trigger ferroptosis via iron oxidation, inhibition of the thioredoxin/thioredoxin reductase system or less defined modes of action.
Bone/cartilage organoid on-chip: Construction strategy and application
Authors: Yan Hu, Hao Zhang, Sicheng Wang, Liehu Cao, Fengjin Zhou, Yingying Jing, Jiacan Su
Journal: Bioactive Materials (2023)

The necessity of disease models for bone/cartilage related disorders is well-recognized, but the barrier between ex-vivo cell culture, animal models and the real human body has been pending for decades. The organoid-on-a-chip technique showed opportunity to revolutionize basic research and drug screening for diseases like osteoporosis and arthritis. The bone/cartilage organoid on-chip (BCoC) system is a novel platform of multi-tissue which faithfully emulate the essential elements, biologic functions and pathophysiological response under real circumstances. In this review, we propose the concept of BCoC platform, summarize the basic modules and current efforts to orchestrate them on a single microfluidic system. Current disease models, unsolved problems and future challenging are also discussed, the aim should be a deeper understanding of diseases, and ultimate realization of generic ex-vivo tools for further therapeutic strategies of pathological conditions.
Repurpose dasatinib and quercetin: Targeting senescent cells ameliorates postmenopausal osteoporosis and rejuvenates bone regeneration
Authors: Ying Wang, Lingbin Che, Xi Chen, Zirui He, Dianwen Song, Yuan Yuan, Changsheng Liu
Journal: Bioactive Materials (2023)

Clinical therapies developed for estrogen-deficiency-driven postmenopausal osteoporosis (PMO) and related diseases, such as bone degeneration, show multiple adverse effects nowadays. Targeting senescent cells (SnCs) and the consequent senescence-associated secretory phenotype (SASP) with a combination of dasatinib and quercetin (DQ) is a recently developed novel therapy for multiple age-related diseases. Herein, we found that estrogen deficiency induced-bone loss was attributed to a pro-inflammatory microenvironment with SASP secretions and accelerated SnC accumulation, especially senescent mesenchymal stem cells (MSCs) characterized by exhaustion and dysfunction in middle aged rats. Systematically targeting SnCs with DQ strikingly ameliorated PMO and restored MSC function. Local administration of DQ and bone morphogenetic protein 2 (BMP2) in combination promoted osteogenic differentiation of MSCs and rejuvenated osteoporotic bone regeneration. Our results repurposed DQ as an attractive therapy for treating PMO and related diseases.
Neurofilament light chain is increased in the parahippocampal cortex and associates with pathological hallmarks in Parkinson’s disease dementia
Authors: Irene Frigerio, Max A. Laansma, Chen-Pei Lin, Emma J. M. Hermans, Maud M. A. Bouwman, John G. J. M. Bol, Yvon Galis-de Graaf, Dagmar H. Hepp, Annemieke J. M. Rozemuller, Frederik Barkhof, Wilma D. J. van de Berg, Laura E. Jonkman
Journal: Translational Neurodegeneration (2023)

Abstract Background Increased neurofilament levels in biofluids are commonly used as a proxy for neurodegeneration in several neurodegenerative disorders. In this study, we aimed to investigate the distribution of neurofilaments in the cerebral cortex of Parkinson’s disease (PD), PD with dementia (PDD) and dementia with Lewy bodies (DLB) donors, and its association with pathology load and MRI measures of atrophy and diffusivity. Methods Using a within-subject post-mortem MRI-pathology approach, we included 9 PD, 12 PDD/DLB and 18 age-matched control donors. Cortical thickness and mean diffusivity (MD) metrics were extracted respectively from 3DT1 and DTI at 3T in-situ MRI. After autopsy, pathological hallmarks (pSer129-αSyn, p-tau and amyloid-β load) together with neurofilament light-chain (NfL) and phosphorylated-neurofilament medium- and heavy-chain (p-NfM/H) immunoreactivity were quantified in seven cortical regions, and studied in detail with confocal-laser scanning microscopy. The correlations between MRI and pathological measures were studied using linear mixed models. Results Compared to controls, p-NfM/H immunoreactivity was increased in all cortical regions in PD and PDD/DLB, whereas NfL immunoreactivity was increased in the parahippocampal and entorhinal cortex in PDD/DLB. NfL-positive neurons showed degenerative morphological features and axonal fragmentation. The increased p-NfM/H correlated with p-tau load, and NfL correlated with pSer129-αSyn but more strongly with p-tau load in PDD/DLB. Lastly, neurofilament immunoreactivity correlated with cortical thinning in PD and with increased cortical MD in PDD/DLB. Conclusions Taken together, increased neurofilament immunoreactivity suggests underlying axonal injury and neurofilament accumulation in morphologically altered neurons with increased pathological burden. Importantly, we demonstrate that such neurofilament markers at least partly explain MRI measures that are associated with the neurodegenerative process.
Alternative polyadenylation regulation in cardiac development and cardiovascular disease
Authors: Jun Cao, Muge N Kuyumcu-Martinez
Journal: Cardiovascular Research (2023)

Cleavage and polyadenylation of pre-mRNAs is a necessary step for gene expression and function. Majority of human genes exhibit multiple polyadenylation sites, which can be alternatively used to generate different mRNA isoforms from a single gene. Alternative polyadenylation (APA) of pre-mRNAs is important for the proteome and transcriptome landscape. APA is tightly regulated during development and contributes to tissue-specific gene regulation. Mis-regulation of APA is linked to a wide range of pathological conditions. APA-mediated gene regulation in the heart is emerging as a new area of research. Here, we will discuss the impact of APA on gene regulation during heart development and in cardiovascular diseases. First, we will briefly review how APA impacts gene regulation and discuss molecular mechanisms that control APA. Then, we will address APA regulation during heart development and its dysregulation in cardiovascular diseases. Finally, we will discuss pre-mRNA targeting strategies to correct aberrant APA patterns of essential genes for the treatment or prevention of cardiovascular diseases. The RNA field is blooming due to advancements in RNA-based technologies. RNA-based vaccines and therapies are becoming the new line of effective and safe approaches for the treatment and prevention of human diseases. Overall, this review will be influential for understanding gene regulation at the RNA level via APA in the heart and will help design RNA-based tools for the treatment of cardiovascular diseases in the future.
The effect of procedural time on dysplasia detection rate during endoscopic surveillance of Barrett’s esophagus
Authors: Mathew Vithayathil, Ines Modolell, Jacobo Ortiz-Fernandez-Sordo, Apostolos Pappas, Wladyslaw Januszewicz, Maria O’Donovan, Michele Bianchi, Jonathan R. White, Philip Kaye, Krish Ragunath, Massimiliano di Pietro
Journal: Endoscopy (2023)

Background Endoscopic surveillance of Barrett’s esophagus (BE) with Seattle protocol biopsies is time-consuming and inadequately performed in routine practice. There is no recommended procedural time for BE surveillance. We investigated the duration of surveillance procedures with adequate tissue sampling and effect on dysplasia detection rate (DDR). Methods We performed post hoc analysis from the standard arm of a crossover randomized controlled trial recruiting patients with BE (≥C2 and/or ≥M3) and no clearly visible dysplastic lesions. After inspection with white-light imaging, targeted biopsies of subtle lesions and Seattle protocol biopsies were performed. Procedure duration and biopsy number were stratified by BE length. The effect of endoscopy-related variables on DDR was assessed by multivariable logistic regression. Results Of 142 patients recruited, 15 (10.6 %) had high grade dysplasia/intramucosal cancer and 15 (10.6 %) had low grade dysplasia. The median procedural time was 16.5 minutes (interquartile range 14.0–19.0). Endoscopy duration increased by 0.9 minutes for each additional 1 cm of BE length. Seattle protocol biopsies had higher sensitivity for dysplasia than targeted biopsies (86.7 % vs. 60.0 %; P = 0.045). Longer procedural time was associated with increased likelihood of dysplasia detection on quadrantic biopsies (odds ratio [OR] 1.10, 95 %CI 1.00–1.20, P = 0.04), and for patients with BE &gt; 6 cm also on targeted biopsies (OR 1.21, 95 %CI 1.04–1.40; P = 0.01). Conclusions In BE patients with no clearly visible dysplastic lesions, longer procedural time was associated with increased likelihood of dysplasia detection. Adequate time slots are required to perform good-quality surveillance and maximize dysplasia detection.
Author Correction: An inflammatory state remodels the immune microenvironment and improves risk stratification in acute myeloid leukemia
Authors: Audrey Lasry, Bettina Nadorp, Maarten Fornerod, Deedra Nicolet, Huiyun Wu, Christopher J Walker, Zhengxi Sun, Matthew T Witkowski, Anastasia N Tikhonova, Maria Guillamot-Ruano, Geraldine Cayanan, Anna Yeaton, Gabriel Robbins, Esther A Obeng, Aristotelis Tsirigos, Richard M Stone, John C Byrd, Stanley Pounds, William L Carroll, Tanja A Gruber, Ann-Kathrin Eisfeld, Iannis Aifantis
Journal: Nature Cancer (2023)
Human early-onset dementia caused by DAP12 deficiency reveals a unique signature of dysregulated microglia
Authors: Yingyue Zhou, Mari Tada, Zhangying Cai, Prabhakar S Andhey, Amanda Swain, Kelly R Miller, Susan Gilfillan, Maxim N Artyomov, Masaki Takao, Akiyoshi Kakita, Marco Colonna
Journal: Nature Immunology (2023)
Genome-wide meta-analysis identifies 93 risk loci and enables risk prediction equivalent to monogenic forms of venous thromboembolism
Authors: Jonas Ghouse, Vinicius Tragante, Gustav Ahlberg, Søren A Rand, Jakob B Jespersen, Eva Birgitte Leinøe, Christoffer Rasmus Vissing, Linea Trudsø, Ingileif Jonsdottir, Karina Banasik, Søren Brunak, Sisse R Ostrowski, Ole B Pedersen, Erik Sørensen, Christian Erikstrup, Mie Topholm Bruun, Kaspar Rene Nielsen, Lars Køber, Alex H Christensen, Kasper Iversen, David Jones, Kirk U Knowlton, Lincoln Nadauld, Gisli H Halldorsson, Egil Ferkingstad, Isleifur Olafsson, Solveig Gretarsdottir, Pall T Onundarson, Patrick Sulem, Unnur Thorsteinsdottir, Gudmundur Thorgeirsson, Daniel F Gudbjartsson, Kari Stefansson, Hilma Holm, Morten Salling Olesen, Henning Bundgaard
Journal: Nature Genetics (2023)
Genome-wide RNA polymerase stalling shapes the transcriptome during aging
Authors: Akos Gyenis, Jiang Chang, Joris J P G Demmers, Serena T Bruens, Sander Barnhoorn, Renata M C Brandt, Marjolein P Baar, Marko Raseta, Kasper W J Derks, Jan H J Hoeijmakers, Joris Pothof
Journal: Nature Genetics (2023)

Gene expression profiling has identified numerous processes altered in aging, but how these changes arise is largely unknown. Here we combined nascent RNA sequencing and RNA polymerase II chromatin immunoprecipitation followed by sequencing to elucidate the underlying mechanisms triggering gene expression changes in wild-type aged mice. We found that in 2-year-old liver, 40% of elongating RNA polymerases are stalled, lowering productive transcription and skewing transcriptional output in a gene-length-dependent fashion. We demonstrate that this transcriptional stress is caused by endogenous DNA damage and explains the majority of gene expression changes in aging in most mainly postmitotic organs, specifically affecting aging hallmark pathways such as nutrient sensing, autophagy, proteostasis, energy metabolism, immune function and cellular stress resilience. Age-related transcriptional stress is evolutionary conserved from nematodes to humans. Thus, accumulation of stochastic endogenous DNA damage during aging deteriorates basal transcription, which establishes the age-related transcriptome and causes dysfunction of key aging hallmark pathways, disclosing how DNA damage functionally underlies major aspects of normal aging.
Nanoparticle biodistribution coefficients: A quantitative approach for understanding the tissue distribution of nanoparticles
Authors: Mokshada Kumar, Priyanka Kulkarni, Shufang Liu, Nagendra Chemuturi, Dhaval K. Shah
Journal: Advanced Drug Delivery Reviews (2023)

The objective of this manuscript is to provide quantitative insights into the tissue distribution of nanoparticles. Published pharmacokinetics of nanoparticles in plasma, tumor and 13 different tissues of mice were collected from literature. A total of 2018 datasets were analyzed and biodistribution of graphene oxide, lipid, polymeric, silica, iron oxide and gold nanoparticles in different tissues was quantitatively characterized using Nanoparticle Biodistribution Coefficients (NBC). It was observed that typically after intravenous administration most of the nanoparticles are accumulated in the liver (NBC = 17.56 %ID/g) and spleen (NBC = 12.1 %ID/g), while other tissues received less than 5 %ID/g. NBC values for kidney, lungs, heart, bones, brain, stomach, intestine, pancreas, skin, muscle and tumor were found to be 3.1 %ID/g, 2.8 %ID/g, 1.8 %ID/g, 0.9 %ID/g, 0.3 %ID/g, 1.2 %ID/g, 1.8 %ID/g, 1.2 %ID/g, 1.0 %ID/g, 0.6 %ID/g and 3.4 %ID/g, respectively. Significant variability in nanoparticle distribution was observed in certain organs such as liver, spleen and lungs. A large fraction of this variability could be explained by accounting for the differences in nanoparticle physicochemical properties such as size and material. A critical overview of published nanoparticle physiologically-based pharmacokinetic (PBPK) models is provided, and limitations in our current knowledge about in vitro and in vivo pharmacokinetics of nanoparticles that restrict the development of robust PBPK models is also discussed. It is hypothesized that robust quantitative assessment of whole-body pharmacokinetics of nanoparticles and development of mathematical models that can predict their disposition can improve the probability of successful clinical translation of these modalities.
Catheter-Based Endomyocardial Injection With Real-Time Magnetic Resonance Imaging
Authors: Robert J. Lederman, Michael A. Guttman, Dana C. Peters, Richard B. Thompson, Jonathan M. Sorger, Alexander J. Dick, Venkatesh K. Raman, Elliot R. McVeigh
Journal: Circulation (2002)

Background — We tested the feasibility of targeted left ventricular (LV) mural injection using real-time MRI (rtMRI). Methods and Results — A 1.5T MRI scanner was customized with a fast reconstruction engine, transfemoral guiding catheter–receiver coil (GCC), MRI-compatible needle, and tableside consoles. Commercial real-time imaging software was customized to facilitate catheter navigation and visualization of injections at 4 completely refreshed frames per second. The aorta was traversed and the left ventricular cavity was entered under direct rtMRI guidance. Pigs underwent multiple injections with dilute gadolinium-DTPA. All myocardial segments were readily accessed. The active GCC and the passive Stiletto needle injector were readily visualized. More than 50 endomyocardial injections were performed with the aid of rtMRI; 81% were successful with this first-generation prototype. Conclusion — Percutaneous endomyocardial drug delivery is feasible with the aid of rtMRI, which permits precise 3-dimensional localization of injection within the LV wall.
Donor Transaminase and Recipient Hepatitis
Authors: Harvey J. Alter
Journal: JAMA (1981)

To assess the relationship of donor alanine aminotransferase (ALT) level to recipient hepatitis, 283 transfused patients were prospectively followed up after open heart surgery; hepatitis developed in 12.7%, of which 97% was non-A, non-B. The ALT tests on 3,359 donors to these patients indicated that risk of hepatitis was significantly associated with the level of donor ALT; 29% of 52 patients receiving at least 1 unit of blood with an ALT level greater than 53 IU/L had hepatitis develop (20.7 cases per 1,000 units), compared with 9% of 231 recipients of only blood with an ALT level of 53 IU/L or less (7.8 cases per 1,000 units). Calculation of corrected efficacy predicts that, at an exclusion level equivalent to 2.25 SDs above the mean log for normal subjects, ALT testing of donors could prevent 29% of posttransfusion hepatitis at the loss of 1.6% of donor units. (<i>JAMA</i>1981;246:630-634)
"Standard Bone": A Description of Radiographic Technique
Authors: George D. Steven
Journal: Annals of the Rheumatic Diseases (1947)

The following is a description of the " Standard Bone" now included in the " standardized radiographs of the hands" of all patients at the Royal National Hospital for Rheumatic Diseases, Bath.Chiefly because this bone is so commonly involved in rheumatoid arthritis, the bone chosen is a second metacarpal of a normal adult.After treatment for defatting in the laboratory, tests were made with the bone embedded in paraffin wax of appropriate thickness-wax being generally considered to have an absorptive effect on x rays equivalent to the soft tissues of the body.These tests, however, showed quite clearly that the absorptive effect of the paraffin wax was less than the tissues, with the result that=the standard bone failed in its purpose as a control to demonstrate the presence of early osteoporosis in rheumatoid arthritis.Further tests were made with a mixture Which is employed in making radium moulds.This consists of paraffiAi -wax (5 parts), beeswax (5 parts) and fine sawdust (I part by weight).The results obtained with this medium were satisfactory.Radiographs of the standard bone are shown in Fig. 1, page 185.The bone is contained in a thin cardboard box which is 3 cm.deep at the knuckle end, and 4 cm.deep at the base or wrist end-corresponding with the measurements of the average adult hand.By acting as a normal control, the standard bone assists in the detection of early osteoporosis.-Italso serves to confirm any x-ray appearance of subsequent progress.In adanced cases it helps to differentiate changes of quiescent rheumatoid arthritis from gou't, as the presence of' generalized osteoporosis may be a deciding factor when these diseases simulate each' other.Fig. 2, page 185, shows a radiograph of the hands of a normal adult with the standard bone in position.
Topical Agents Alone in Acne
Authors: Leonard J. Swinyer
Journal: JAMA (1980)

The comparative effectiveness of three comprehensive therapeutic programs was studied in 118 patients with mild to moderate acne vulgaris. A topical program of tretinoin, benzoyl peroxide, and water avoidance was found to be as effective as the more commonly employed program of systemic tetracycline therapy with topically applied tretinoin and better than a program using systemic tetracycline therapy with abradant cleansers. At 16 weeks of therapy for all groups, the degree of skin dryness correlated with lack of improvement. Skin dryness is established as an aggravating factor in both the pathogenesis and treatment of acne. The topical program was nonirritating, well accepted by patients, and less expensive than the other two regimens. (<i>JAMA</i>243:1640-1643, 1980)
The Inhibitory Quotient
Authors: Paul D. Ellner
Journal: JAMA (1981)

A method for reporting minimum inhibitory concentration (MIC) data that facilitates interpretation by the clinician unfamiliar with clinically achievable drug levels is described. This system uses the inhibitory quotient, which is a number reflecting the multiple of the MIC that would be achieved. Inhibitory quotients are determined for blood, urine, bile, and CSF and reflect achievable drug levels in those body fluids. The use of inhibitory quotients can be extremely helpful to the physician in the rational selection of an appropriate antimicrobial agent. (<i>JAMA</i>1981;246:1575-1578)